Increased analgesic potency of mu agonists after continuous naloxone infusion in rats

Chronic opioid antagonist administration increases opioid binding sites and potentiates behavioral responses to morphine. The present study was designed to examine in rats the temporal and dosage parameters of naloxone-induced potentiation of morphine analgesia and the effect of continuous infusion of naloxone on the analgesic potency of other mu agonists. Cumulative dose-response curves were generated in a tail-flick procedure for each drug tested. Naloxone-filled osmotic pumps were then implanted s.c. for 1 week after which the rats were retested with the agonist. The potency ratio of morphine (ED50 before naloxone/ED50 after naloxone) showed orderly increases over a range of naloxone doses (0.03-1.0 mg/kg/hr) and increased, then decreased, over a range of time points (6-72 hr) after removal of the osmotic pumps. The relative potency of morphine was 2.1 at 24 hr after a 7-day infusion of 0.3 mg/kg/hr of naloxone. These parameters were then used in tests of other mu agonists. Five drugs produced maximum increases in tail-flick latencies before naloxone. Of these, naloxone increased the analgesic potency of fentanyl, methadone and levorphanol (relative potencies ranged from 1.7-2.1) but not of etorphine and propoxyphene. The naloxone infusion increased the maximum analgesic effect of meperidine, profadol and pentazocine, but had no effect on the analgesic activity of buprenorphine, butorphanol, ethylketocyclazocine and nalbuphine. Our results demonstrate that 7-day naloxone infusion increases the analgesic potency of some, but not all, opioids with mu agonist activity.